Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[Cl:10][C:11]1[N:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([N:21]3[CH:25]([O:26][C:27](OC4C=CC=CC=4)=[O:28])[C:24]4[S:36][CH2:37][CH2:38][O:39][C:23]=4[C:22]3=[O:40])=[N:18]2)=[CH:13][CH:12]=1.C(OC(C)C)(C)C>C(#N)C>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:27]([O:26][CH:25]2[N:21]([C:17]3[CH:16]=[CH:15][C:14]4[C:19](=[N:20][C:11]([Cl:10])=[CH:12][CH:13]=4)[N:18]=3)[C:22](=[O:40])[C:23]3[O:39][CH2:38][CH2:37][S:36][C:24]2=3)=[O:28])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCNCC1
Reactant: O=C(Oc1ccccc1)OC1C2=C(OCCS2)C(=O)N1c1ccc2ccc(Cl)nc2n1
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: C=CCN1CCN(C(=O)OC2C3=C(OCCS3)C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Reaction time: 29 h
Yield: 63.5 %

Procedure:
1-Allylpiperazine (6.3 g.) is added to a suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-5-phenoxycarbonyloxy-2,3,6,7-tetrahydro-5H-1,4-oxathiino[2,3-c]pyrrole (4.56 g.) in acetonitrile (25 cc.). The temperature of the reaction mixture rises to about 25° C. After 29 hours, diisopropyl ether (50 cc.) is added and the insoluble product is filtered off and washed with diisopropyl ether (2 × 15 cc.). After drying, 5-(4-allylpiperazine-1-yl)carbonyloxy-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-1,4-oxathiino[2,3-c]pyrrole (3.1 g.), melting at 254° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23].C(=O)([O-])[O-].[K+].[K+].I[CH:34]([CH3:36])[CH3:35]>O>[C:19]([C:4]1[C:3]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:2]([NH:1][CH:34]([CH3:36])[CH3:35])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: CC(C)I
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)Nc1c(C(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoroacetylpyrazole (1 g) in anhydrous N,N-dimethylformnamide (4 ml) at room temperature was added potassium carbonate (0.7 g), then 2-iodopropane (190 μl). The mixture was stirred at room temperature for 48 hours. Water (50 ml) was then added, and the mixture was extracted with ether (50 ml, ×2). The combined organic layers were washed with water (50 ml), dried (Na2SO4) filtered and evaporated. The residue was purified by column chromatography on silica gel (50 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a very pale yellow solid, m.p 136-137° C.
Reaction SMILES: [CH3:1][NH2:2].C1COCC1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][CH:10]=1>O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:2][CH3:1])=[O:17])=[CH:11][CH:10]=1
Reactant: CN
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)Cc1ccc(F)cc1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of methylamine in THF (2.0 M, 5 mL, 10 mmol) was added 4-fluorophenylacetyl chloride (518 mg, 3.0 mmol) at −78° C. The reaction mixture was stirred from −78° C. to room temperature for 1 h. The solution was diluted with H2O and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. Filtration, followed by concentration, provided the title compound (490 mg, 98%). MS(ESI+) m/z 168 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[F:20]>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:15][C:14]=1[F:20]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1ccc(Cl)c(F)c1
Product: N#Cc1cc(C=O)ccc1Oc1ccc(Cl)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 4-chloro-3-fluorophenol.
Reaction SMILES: C(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:14][N:15]([C:23]1[CH:28]=[C:27]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24]=1[N+:40]([O-])=O)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>O.O1CCOCC1>[NH2:40][C:24]1[CH:25]=[CH:26][C:27]([O:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=2)=[CH:28][C:23]=1[N:15]([CH3:14])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1N

Procedure:
Sodium bicarbonate (4.2 g) and sodium dithionite (3.5 g) were added to a solution of t-butyl N-methyl-N-[5-(4-trifluoromethylphenoxy)-2-nitrophenyl]carbamate in water/dioxane=1/5 (60 ml). The mixture was heated at reflux for 1 hour. At the end of this time the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane/ethyl acetate=3/1-2/1 as the eluant to give the title compound (0.7 g).
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2]1.[H-].[Na+].Cl[CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27].CCOC(C)=O>CN(C=O)C>[CH3:29][N:28]([CH3:30])[C:26](=[O:27])[CH2:25][N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH2:1][CH2:2][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][CH2:5][C:6]1=2
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2CC1
Reactant: CN(C)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
tert-Butyl 1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.100 g, 0.349 mmol) was dissolved in DMF (1.0 mL) under N2 at rt. NaH (0.0450 g, 1.13 mmol, 3.22 equiv., 60% dispersion) was added and the mixture was stirred at rt for 30 min. 2-Chloro-N,N-dimethylacetamide (86 μL, 0.102 g, 0.838 mmol, 2.4 equiv.) was added, and the reaction mixture was stirred at rt for 24 h. The reaction mixture was poured over ice, thenextracted with EtOAc (2×). The organic extracts was washed first with water, then with brine and dried over MgSO4. The organic extracts was filtered and concentrated to yield a crude product (0.148 g). The crude product was chromatographed (SiO2 18 g, eluted with 3:1 toluene:acetone) to give tert-butyl 6-[2-(dimethylamino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.116 g) in 90% yield. 1H NMR (300 MHz, CDCl3) δ 1.50, 2.87-2.95, 3.01, 3.00-3.07, 3.13, 3.68-3.80, 4.85, 7.07-7.19, 7.47-7.51; MS (ESI+) for C21H29N3O3 m/z 372.2 (M+H)+.
Reaction SMILES: I[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Ic1sc2ccccc2c1Oc1ccc(OCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cccc(-c2sc3ccccc3c2Oc2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To a solution of 2-iodo-3-(4-benzyloxyphenoxy)benzo[b]thiophene (5.00 g, 11.0 mmol) in 50 mL of toluene under N2 were added 3-methoxyphenylboronic acid (2.00 g, 13.0 mmol), (Ph3P)4Pd (0.75 g, 0.66 mmol), and 18.0 mL of 2.0N Na2CO3 solution. The resulting mixture was heated to reflux for 2 h. Upon cooling to room temperature, the reaction was diluted with EtOAc and extracted several times with 0.1N NaOH. The organic was then dried (Na2SO4) and concentrated in vacuo to an oil. Chromatography (SiO2, 0-10% Et2O/hexanes) provided 4.8 g (99%) of 2-(3-methoxyphenyl)-3-(4-benzyloxyphenoxy)benzo[b]thiophene as a brown oil.
Reaction SMILES: C(O)(=O)C.N1C=CC=CC=1.[F:11][C:12]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:13]=1[CH:14]=O.[OH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[O:25][C:24](=[O:32])[CH:23]=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([SH:40])=[CH:36][CH:35]=1>C(O)C>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([S:40][CH:14]([C:13]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:12]=2[F:11])[C:23]2[C:24](=[O:32])[O:25][C:26]3[C:31]([C:22]=2[OH:21])=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:36][CH:35]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: O=Cc1cc(F)ccc1F
Solvent: CCO
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=c1oc2ccccc2c(O)c1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Reaction time: 24 h

Procedure:
At room temperature, glacial acetic acid (60 mg, 1 mmol) and pyridine (80.5 μl, 1 mmol) were added to an ethanol (4 ml) solution of 2,5-difluorobenzaldehyde (109 μl, 1 mmol), 4-hydroxycoumarin (162 mg, 1 mmol) and 4-chlorothiophenol (144.6 mg, 1 mmol) and the mixture was stirred for 24 hours. The precipitate thus formed was collected by filtration and washed with a small amount of ethanol, whereby the title compound (345 mg, 80%) was obtained as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-:3])=O.[CH2:16]=[CH:17][CH:18]=[CH2:19]>>[OH:3][NH:1][C:4]1[C:5]2[C:6](=[O:15])[C:7]3[C:8](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9](=[O:14])[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: C=CC=C
Product: O=C1c2ccccc2C(=O)c2c(NO)cccc21

Procedure:
5-Nitro-1,4-naphthoquinone, referred to hereinafter for short as 5-nitronaphthoquinone, is an important dyestuff intermediate which is reacted with butadiene by a Diels-Alder reaction to 5-nitro1, 1,4,11,12-tetrahydroanthraquinone (q.v. for example N.N. Vorozhtsov et al., Zhur. Vsesoyuz. Khim. Obshchestva in D.I. Mendeleeva 5, 474 (1960) - Chem. Abstract, Vol. 55, 1547e), which is subsequently rearranged to give 1-hydroxyaminoanthraquinone or converted direct to 1-aminoanthraquinone, the starting material for numerous disperse and vat dyes (e.g. German Offenlegungsschrift 24 50 883).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH2:48][CH3:49])[N:26]=[C:25]2[CH3:50])=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14]>O>[C:13]([O:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:36][CH:37]=3)=[C:27]([CH2:46][CH2:47][CH2:48][CH3:49])[N:26]=[C:25]2[CH3:50])=[CH:22][CH:23]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(-c2ccc(OC(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(-c2ccc(OC(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogen carbonate (1.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[1-(4-tert-butoxyphenyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.51 g) was added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.27 g, 48%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[I:11][CH2:12][CH3:13]>>[I-:11].[CH2:12]([N+:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3][C:2]=1[CH3:1])[CH3:13]
Reactant: Cc1nc2ccccc2o1
Reactant: CCI
Product: CC[n+]1c(C)oc2ccccc21
Product: [I-]

Procedure:
3 ethyl-2-methyl-benzoxazolium iodide was prepared by heating 2-methyl-benzoxazole with iodoethane under reflux.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)([OH:15])[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[N+:22]([O-:25])([OH:24])=[O:23]>C(O)C.C(O)(C)C>[N+:22]([O-:25])([O-:24])=[O:23].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:13]([C:16]3[CH:17]=[CH:18][NH+:19]=[CH:20][CH:21]=3)([OH:15])[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC(O)(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Solvent: CCO
Solvent: CC(C)O
Product: CC(O)(c1cc[nH+]cc1)c1cnc(-c2ccc(F)cc2)s1
Product: O=[N+]([O-])[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A suspension of 1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol (2 g, 10 mmol) in ethanol (6 mL) and isopropyl alcohol (30 mL) was cooled to 0° C., and to this mixture was added 6N HNO3 (6 mL) in 30 mL of isopropyl alcohol. The reaction mixture was stirred for 1 hour at room temperature. The solid formed was filtered and washed with hexane (10 mL) to afford 4-(1-(2-(4-fluorophenyl)thiazol-5-yl)-1-hydroxyethyl)pyridin-1-ium nitrate as an off-white solid (2.3 g, 63% yield), HPLC purity 99.8%, mp 188-191° C. 1H NMR (400 MHz, DMSO-d6): 8.85 (d, 2H), 8.10 (d, 2H), 7.92 (t, 3H), 7.30 (t, 2H), 7.13 (br s, 1H), 2.01 (s, 3H); LC-MS m/z calculated for [M+H]+301.07. found 301.1.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[CH2:13][NH2:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([C:26](Cl)=[O:27])[CH:25]=1)[O:22][CH2:21][CH2:20][CH2:19]2>C(C(C)=O)C>[C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[CH2:13][NH:14][C:26]([C:24]2[CH:25]=[C:16]([Cl:15])[CH:17]=[C:18]3[C:23]=2[O:22][CH2:21][CH2:20][CH2:19]3)=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(Cl)c1cc(Cl)cc2c1OCCC2
Reactant: NCC1CCCN1CC1=CCCCC1
Solvent: CCC(C)=O
Product: O=C(NCC1CCCN1CC1=CCCCC1)c1cc(Cl)cc2c1OCCC2
Temperature: 5 °C

Procedure:
101 g of 1-cyclohexenylmethyl-2-aminomethylpyrrolidine and 200 ml of methyl ethyl ketone were introduced into a 2-liter round-bottomed flask. The contents were cooled to 5° C. and a solution of 109 g of 6-chlorochroman-8-carbonyl chloride in 500 ml of methyl ethyl ketone was added dropwise, while maintaining the temperature between 0° and 5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[NH2:13])[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.[CH:25]([S:28](Cl)(=[O:30])=[O:29])([CH3:27])[CH3:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:28]([CH:25]([CH3:27])[CH3:26])(=[O:30])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCCC1c1cccc(F)c1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1cccc(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask equipped with a magnetic stirrer was charged with (+,−) cis-[2-(3-fluoro-phenyl)-cyclopentylamine (650 mg, 3.63 mmol) from preparation 14, methylene chloride (15.0 mL) and the solution cooled to 0° C. DBU (0.65 mL, 4.35 mmol) and isopropylsulfonyl chloride (0.49 mL, 4.35 mmol) were added. The reaction was then stirred at 0° C. for 60.0 minutes and brought to room temperature with stirring overnight. The reaction was diluted with methylene chloride and washed with 1N HCl, brine and the organic layer dried over sodium sulfate. The title compound.was purified by radial chromatography eluting with methylene chloride to give 573 mg (55%) of the purified title compound as a white solid. The nmr was consistent with the assigned structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH:46]([C:48]1[N:53]2[N:54]=[CH:55][N:56]=[C:52]2[CH:51]=[CH:50][N:49]=1)[NH2:47].C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11](=[O:13])[NH:47][NH:46][C:48]1[N:53]2[N:54]=[CH:55][N:56]=[C:52]2[CH:51]=[CH:50][N:49]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: NNc1nccc2ncnn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NNc1nccc2ncnn12)Cc1cc(F)c(F)cc1F
Reaction time: 0.25 h

Procedure:
A solution of 133 mg (0.4 mmol) of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3), 84.5 mg (0.44 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 71 mg (0.5 mmol based on 95% purity) of 1-hydroxybenzotriazole (HOBT) in 1.5 mL of anhydrous DMF was stirred at room temperature in a stoppered flask. After 15 min, this solution was added dropwise by syringe through a septum to a stirred suspension of 72.1 mg (0.48 mmol) of 5-hydrazino[1,2,4]triazolo[1,5-c]pyrimidine (Intermediate 20) 0.209 mL (155 mg, 1.2 mmol) of N,N-diisopropylethylamine in 1 mL of anhydrous DMF. Stirring under nitrogen was continued for 17 h. The mixture was then filtered and concentrated under vacuum. The residue was partitioned between ethyl acetate and 5% aqueous citric acid solution. The organic phase was washed with more 5% citric acid, then with water, and finally with saturated aqueous sodium carbonate solution. The organic solution was dried over magnesium sulfate, filtered and concentrated to yield the title compound as an off-white solid, mp 207.5-209.5° C. LC-MS 488 (M+Na), 366 (M+1-Boc).
Reaction SMILES: [NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18](O)=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH:46]1[CH2:57][CH2:56][CH2:55][C@H:47]1[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49]>O1CCCC1.CN(C)C=O>[NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([N:46]1[CH2:57][CH2:56][CH2:55][C@H:47]1[C:48]([O:50][C:51]([CH3:53])([CH3:54])[CH3:52])=[O:49])=[O:19])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 18 h

Procedure:
15.5 g of Z-Gly-Phe-Gly-OH [manufactured according to J. R. Vaughan & J. A. Eichler, J.Am.Chem.Soc. 75, 5556 (1953)] are dissolved in 100 ml of absolute tetrahydrofurane and 5.3 ml of absolute triethylamine and 4.64 ml of isobutyl chlorocarbonate are added dropwise to the solution cooled to -20°C, whilst stirring, in such a way that the internal temperature does a way that the internal temperature does not exceed -15°C. Thereafter the mixture is allowed to react for 10 minutes at -10°C, is then again cooled to -20°C, and a solution of 7.6 g of H-Pro-OtBu in 30 ml of dimethylformamide is added dropwise whilst stirring, in such a way that the internal temperature does not exceed 0°C. The mixture is allowed to stand for 18 hours at 0°C, the triethylamine hydrochloride is then filtered off and the filtrate is evaporated at 40°C bath temperature. The residue is dissolved in 200 ml of ethyl acetate and the solution is washed with sodium bicarbonate solution, water, 10 % strength tartaric acid solution and water, dried with sodium sulphate and evaporated. The residue is crystallised from ethyl acetate-petroleum ether, melting point 66°- 71°C; [α]D20 = - 45° (c = 1% in chloroform).
Reaction SMILES: [C:1](OC=C)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl[C:11]([Cl:16])([Cl:15])[C:12](Cl)=[O:13].[O-][Mn](=O)(=O)=O.[K+].[CH3:23][CH2:24][O:25]CC>[Zn]>[C:1]([O:13][CH:12]1[CH2:23][C:24](=[O:25])[C:11]1([Cl:16])[Cl:15])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=COC(=O)C(C)(C)C
Reactant: CCOCC
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Zn]
Product: CC(C)(C)C(=O)OC1CC(=O)C1(Cl)Cl
Temperature: 22.5 °C

Procedure:
To a stirred mixture of vinyl pivalate (30 g, 234 mmol) and zinc (31 g, 468 mmol) in ether (300 ml) was added a solution of 2,2,2-trichloroacetyl chloride (55 g, 304 mmol) in ether (300 ml) dropwise (2-3 h) in a water bath. (Note: fast addition causes the reaction temp to elevate) while maintaining the reaction temperature between 15-30° C. After the reaction was done (stained with KMnO4 solution), it was filtered through Celite. The filtrate was washed with cold water, brine, dried over MgSO4 and concentrated to give the title compound as an orange solid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])=O.[H-].[Na+].ClC1[N:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([O:25][CH3:26])[N:18]=1.[OH-].[Na+]>O1CCCC1>[CH3:26][O:25][C:19]1[N:20]=[C:21]([O:23][CH3:24])[N:22]=[C:1]([NH:3][C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=2[N+:11]([O-:13])=[O:12])[N:18]=1
Reactant: Cc1ccc(NC=O)c([N+](=O)[O-])c1
Reactant: COc1nc(Cl)nc(OC)n1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1nc(Nc2ccc(C)cc2[N+](=O)[O-])nc(OC)n1
Reaction time: 0.17 h
Yield: 86.1 %

Procedure:
N-formyl-4-methyl-2-nitroaniline (7.2 g) was dissolved in tetrahydrofuran (50 ml), and sodium hydride (60% purity, oily) (2.0 g) was added thereto at room temperature. After stirring for 10 minutes, 2-chloro-4,6-dimethoxy-[1,3,5]triazine (7.0 g) was added at room temperature, followed by stirring for 3 hours. A 10% aqueous sodium hydroxide solution was added thereto, and the crystals were collected by filtration, washed with water and dried to obtain 10.0 g of the desired product as a yellow powder (m.p. 189-191° C.)